The exact role of creatine kinase (CK) in the biochemical mechanism of high-energy phosphate metabolism as well as its role in supporting myocardial function remain unlear despite considerable experimental effort. We have begun to address these points from the prospective of negative contrast. We have produced an experimental model which allows us to ask the question, "What difference does the absence of creating kinase make to a heart?". We have been successful in totally inhibiting CK in isolated perfused rat hearts by very brief exposure to low concentrations of perfusate-born iodoacetamide. At minimal levels of work in the control state, such hearts maintain normal function as well as normal concentrations of the high-energy phosphates, CrP and ATP. We propose to use this model to define 1) differences in function and metabolism in hearts in the control state with and without inhibition; 2) differences between inhibited and non-inhibited hearts during transient graded ischemia, transient graded hypoxia and transient graded acidosis and during recovery from these results; 3) the differences in function and metabolism between inhibited and non-inhibited hearts from spontaneously hypertensive rats during developing hypertrophy, stable compensated hypertrophy and hypertrophy with failure; and 4) methods to specifically inhibit individual localized CK isozymes such as the mitochondrial and MM isozymes.